A critical research chemoradiation, and the lack of predictive markers for identifying those likely to respond. Advanced laryngeal cancer is a devastating disease for which better therapies are needed. Surgery is effective in some patients but the surgical defects can be functionally and cosmetically unacceptable and many patients recur after surgery. Thus, the development of predictive markers to select patients for appropriate therapy is needed. Our preliminary results suggest that p53 expression or mutation and expression of the apoptosis-blocking proteins, BCL-2 and BCL-xL, interact to determine responsiveness to chemoradiation. We propose to determine in patients with advanced laryngeal cancer treated on the multi-institutional, randomized Department of Veterans Affairs Laryngeal Cancer Study whether chemotherapy response, organ preservation and/or survival is predicted by p53 overexpression and gene mutation, and we will determine how this is influenced by the expression of BCL-2 and BCL-xL. Our preliminary in vivo and in vitro data support the concept that tumors with mutant p53 are susceptible to cisplatin-based chemotherapy regimens but that those with wild type p53 are resistant. We will test our hypotheses in tumor samples obtained from patients before and after organ-sparing therapy and we will test these hypotheses with in-vitro experiments using cell lines with known p53 and BCL-2/BCL-xL status. The mechanism of cell death (apoptosis-dependent or independent) may determine the efficacy of different interventions and dictate which treatments are appropriate. The information acquired in this work should result in new trials that employ predictive markers to select the most appropriate and effective treatment for advanced laryngeal cancer.